TDP-43 is a developmentally regulated protein essential for early embryonic development

TDP-43 is a DNA/RNA-binding protein implicated in multiple steps of transcriptional and post-transcriptional regulation of gene expression. Alteration of this multifunctional protein is associated with a number of neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin positive inclusions. Whereas a pathological link to neurodegenerative disorders has been established, the cellular and physiological functions of TDP-43 remain unknown. In this study, we show that TDP-43 is a nuclear protein with persistent high-level expression during embryonic development and with progressively decreased protein levels during postnatal development. In mice where the TDP-43 gene (Tardbp) was disrupted using a gene trap that carries a β-galactosidase marker gene, heterozygous (Tardbp^+/-) mice are fertile and healthy, but intercrosses of Tardbp^+/- mice yielded no viable homozygotic null (Tardbp^+/-) mice. Indeed, Tardbp^+/- embryos die between 3.5 and 8.5 days of development. Tardbp^+/- blastocysts grown in cell culture display abnormal expansion of their inner cell mass. The pattern of β-galactosidase staining at E9.5 Tardbp^+/- embryos is predominantly restricted to the neuroepithelium and remains prominent in neural progenitors at E10.5-12.5. TDP-43 is detected in spinal cord progenitors and in differentiated motor neurons as well as in the dorsal root ganglia at E12.5. β-Galactosidase staining of tissues from adult Tardbp^+/- mice shows widespread expression of TDP-43, including prominent levels in various regions of the central nervous system afflicted in neurodegenerative disorders. These results indicate that TDP-43 is developmentally regulated and indispensible for early embryonic development.